9 10-secogona-1 3 5(10) 8(14)-tetraene-9-ones

ABSTRACT

THIS INVENTION RELATES TO AN OPTICALLY ACITVE SECO-GONATETRAENE OF THE FORMULA   1,1-(-O-R&#34;-O-),4-((2-R4,3-(R3-O-),4-R2,S-R1-PHENYL)-   CH(-R5)-CH(-R6)-),5-(O=),7A-R-5,6,7,7A-TETRAHYDROINDAN   WHERE R IS AN ALKYL HAVING 1 TO 3 CARBON ATOMS, R&#34; IS A LOWER ALKYLENE HAVING 2 TO 4 CARBON ATOMS, R1, R2 AND R4 ARE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL AND LOWER ALKOXY, R3 IS LOWER ALKYL, R5 AND R6 ARE SUBSTITUENTS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, A-LOWER ALKYL AND B-LOWER ALKYL AND THE WAVY LINE INDICATES EITHER THE A-CONFIGURATION OR THE B-CONFIGURATION, WHICH ARE USED AS INTERMEDIATES IN THE PREPARATION OF OPITCALLY ACTIVE 13-ALKYL GONAPENTAENES.

United States Patent @fice 3,637,7549,10-SECOGONA-1,3,5(),8(14)-TETRAENE-9-0NES Robert Bucourt,Clichy-sous-Bois, Michel Vignau, N euillysur-Seine, and Jean Raynal,Paris, France, assignors to Roussel-UCLAF, Paris, France No Drawing.Original application Aug. 21, 1967, Ser. No. 661,786, now Patent No.3,506,693, dated Apr. 14, 1970. Divided and this application Jan. 21,1970, Ser. No. 8,119

Claims priority, application France, Aug. 25, 1966, 74,179; Nov. 25,1966, 85,043; July 7, 1967, 113,579 Int. Cl. C07d 13/04 U.S. Cl.260-3403 3 Claims ABSTRACT OF THE DISCLOSURE This invention relates toan optically active seco-gonatetraene of the formula where R is an alkylhaving 1 to 3 carbon atoms, R is a lower alkylene having 2 to 4 carbonatoms, R R and R are substituents selected from the group consisting ofhydrogen, lower alkyl and lower alkoxy, R is lower alkyl, R and R aresubstituents selected from the group consisting of hydrogen, wloweralkyl and it-lower alkyl and the wavy line indicates either thea-configuration or the p-configuration, which are used as intermediatesin the preparation of optically active l3-alky1 gonapentaenes.

This application is a divisional of application Ser. No. 661,786, filedon Aug. 21, 1967, now Pat. No. 3,506,693.

More particularly, the invention relates to a novel process for thepreparation of the 13 8-R-A -gonapentaenes of the general Formula IXOHgO wherein R represents an alkyl radical comprising from 1 to 3 carbonatoms.

The l3fl-R-A -gonapentaenes of the general Formula IX, described in US.Pat. No. 3,202,686, possess interesting hormonal effects. Thesecompounds are estrogens acting in a favorable manner on the amount ofthe blood lipids.

It is a well-known fact that the object, always searched for by thesteroid chemist, is to discover a process for the synthesis which,although being linear and branched, has a sufficiently convergentcharacter, whereby, on the other hand, the reaction may bestereospecific in the desired sense, and which allows a rapidresolution, preferably with the possibility of recovery of the undesiredisomer. But whereas certain published syntheses up to this day respondto one or the other of these desiderata, a very small 3,637,754 PatentedJan. 25, 1972 number is known to realize, these needs in a simultaneousmanner.

The process of the invention offers several advantages and isdistinguished, among other factors, by a very pronounced characteristicof convergence. In fact, in this process, two molecules each comprisinghalf of the carbon skeleton of estrone are combined, the synthesis ofwhich is completed in a limited number of steps. Moreover, the inventionaffords the possibility to proceed, after the first three operationalsteps have been accomplished, to the resolution into optically activeisomers, and this is done with the recovery of the undesired isomer, aconsiderable advantage of the present process, by a rearrangement whichrestores it to a structure, wherein the substance is inactive by nature.Another advantage of the present process exists in the fact of requiringonly a few stereospecific reactions, which, in addition, can be realizedwith satisfactory yields.

OBIECTS OF THE INVENTION An object of the present invention is thedevelopment of a method for the stereospecific synthesis of B S-alkyl- A-gonapentaene-l7-ones utilizing an early reso-,

lution into the desired optical antipodes of natural configuration.

Another object of the present invention is the development of a processfor the preparation of an optically active 13-alkyl gonapentaene of theformula Q? I a.

wherein R has the above-noted meanings, with a vinyl compound of theformula CH =CHY wherein Y is a. substituent selected from the groupconsisting of -COO-- lower alkyl and --Cr-N, in an anhydrous alkalinemedium:

(b) Ketalizing the resultant cyclopentylpropionyl compound of theformula wherein R and Y have the above-noted meanings by the action of aketalizing agent selected from the group consisting of lower alkyleneglycols and dioxolanes, where the lower alkylene has from 2 to 4 carbonatoms, under ketalizing conditions,

(c) Saponifying the resultant d,l-ketal of the formula wherein R and Yhave the above-noted meanings and R" represents a lower alkylene having2 to 4 carbon atoms by the action of an aqueous alkaline medium;

(d) Resolving the resultant d,l-cyclopentyl-propionic acid of theformula HOOOQ wherein R and R have the above-noted meanings into itsoptical antipodes by the action of an optically active base; (e)Lactonizing the resultant optically-active isomer ofcyclopentyl-propionic acid of the formula wherein R and R have theabove-noted meanings by the action of a lactonizing agent;

(i) Condensing the resultant optically active lactone of 3 (1R-2'-X'-5'-hydroxy-4'-cyclopentyl)propionic acid where R has theabove-noted meanings and X is where 'R" has the above-noted meaningswith a phenylpropyl magnesium halide of the formula R2- MEX R O- R I Ruwherein R, R R R R R R and R" have the abovenoted meanings, by theaction of a strong acid dehydrating agent; and

(h) Recovering said optically active 13-alkylgonapentaene.

A yet further object of the present invention is the obtention of thenovel intermediates;

4 (a) A cyclopentylpropionyl compound of the formula where R is an alkylhaving 1 to 3 carbon atoms and Y is a substituent selected from thegroup consisting of -COO- lower alkyl and C=N;

(b) A cyclopentylpropionyl ketal of the formula where R is an alkylhaving 1 to 3 carbon atoms, Y is a substituent selected from the groupconsisting of COO lower alkyl and CEN and R" is a lower alkylene having2 to 4 carbon atoms;

(0) A cyclopentylpropionic acid of the formula 0 R U 0 H000 where R isan alkyl having from 1 to 3 carbon atoms and R" is a lower alkylenehaving 2 to 4 carbon atoms, selected from the group consisting of theracemate and the optically active isomers, and their salts withoptically active bases;

(d) An optically active lactone of the formula where R is an alkylhaving 1 to 3 carbon atoms, R" is a lower alkylene having 2 to 4 carbonatoms and the wavy line indicates either the d-COIIfigUIatlOII or the)8- configuration;

-(e) An optically active seco-gonatetraene of the formula R 0 Re where Ris an alkyl having 1 to 3 carbon atoms, R" is a lower alkylene having 2to 4 carbon atoms, R R and R are substituents selected from the groupconsisting of hydrogen, lower alkyl and lower alkoxy, R is lower alkyl,R and R are substituents selected from the group consisting of hydrogen,u-lOWCl' alkyl and fi-lower alkyl and the wavy line indicates either thea-configuration or the B-configuration.

These and other objects of the invention will become apparent as thedescription thereof proceeds.

DESCRIPTION OF THE INVENTION The process for the preparation of theoptically active 13-alkyl-gonapentaenes of the general formula wherein Rrepresents an alkyl radical having from 1 to 3 carbon atoms, wherein the1-, 2- and/or 4-position is lower alkoxyl radical or a lower alkylradical can be found, wherein the 6- and/or 7-position a lower alkylradical, such as methyl, can be found in the alpha or betaconfiguration, wherein the 3-position a lower alkoxyl radical instead ofthe methoxyl radical can be found, is characterized in that aZ-R-cyclopentane-1,3-dione is condensed with an alkyl acrylate, thealkyl radical having from 1 to 6 carbon atoms, by working in alkalinemedium; thus obtaining the corresponding alkyl 3-(1'-R-2',5'-dioxocyclopentyl)-propionate, which is then reacted with aketalization agent; the resultant alkyl dl-3-(l-R-2'-X-5'-oxocyclopentyl)-propionate is saponified, X representing the/BII group, wherein R" indicates an alkylene radical having from 2 to 4carbon atoms, substituted or unsubstituted, with the aid of an alkalineagent; the resolution of the resultantdl-3-(l-R-2'-X'-5'-oxo-cyclopentyl) propionic acid into its opticalantipodes is conducted with the aid of an optically active base, such asD()-threo-(1-p.- nitrophenyl) 2 N,N dimethylamino-propane-l,3-diol,L(+)-threo-(1-p.-nitrophenyl) 2 N,N dimethylaminopropane-1,3-diol,cinchonine, yohimbine, l-nor-adrenaline, quinine or l-ephedrine; theisolated optically active 3-(l-R-2'-X-5'-oXo-cyclopentyl)-propionic acidis subjected to the action of a lactonization agent, to obtain thecorresponding optically active lactone of 3-(1-R-2'-X-'-hydroxy-4'-cyclopentenyl)-propionic' acid, which is then condensedwith a 3-m-methoxy-phenyl-prop-yl magnesium halide, selected from thegroup consisting of the bromide, the chloride and the iodide; thecondensation product is subjected to the action of an alkaline agent,thus obtaining the corresponding optically active3-incthoxy-13-R-l7-X'-9,l0 seco A -gonatetraene- 9-one; this lattercompound is subjected to the action of a cyclization agent, and thedesired optically active 3-incthoxy-l3-R-A -gonapentaene-l7-one isisolated.

The process of the invention, relating more particularly to thepreparation of the compounds of the general Formula IX is summarized inTable I, wherein the diverse substituents have the previous meanings,and wherein R represents an alkyl radical comprising from 1 to 6 carbonatoms.

TABLE I R CH2 I 0 H6 II I R n ROOJ? {III R R I X p o v vo OJ o i Thesaid process is characterized in that a Z-R-cyclopentane-1,3-dione (I)is condensed with an alkyl acrylate (II, R'=alkyl having 1 to 6 carbonatoms), working in an alkaline medium, preferably an anhydrous alkalinemedium such as an amine in an inert anhydrous organic solvent, forexample a trialkylamine such as triethylamine in ethyl acetate, toobtain the alkyl 3-(l-R-2',5'-dioxocyclopentyl)-propionate (III, R=a1kylhaving 1 to 6 carbon atoms), (inactive by nature). This latter compoundis reacted with a ketalization agent. The resultant alkyl dl 3(lR-2-X-5-oxo-cyclopentyl)-propionate (IV, R=alkyl having 1 to 6 carbonatoms) is saponified with the aid of an aqueous alkaline agent. Theresolution of the dl 3 (1R-2'-X'-5'-oxo-cyclopentyl)-propionic acidobtained (V) into their optical antipodes is conducted with the aid ofan optically active base. The isomer of the natural configuration of 3(l'-R-2-X-5 oxo cyclopentyl)-propionic acid (V-A), is subjected to theaction of a lactonization agent. The corresponding lactone of the 3(1-R-2-X-5'-hydroxy-4'-cyclopentenyl)-propionic acid (VI) is obtained,which is condensed with a 3-mmethoxy-phenyl-propyl magnesium halide(VII, halide: Hal). The condensation product is subjected to the actionof an alkaline agent, thus obtaining 3-methoxy-l3/3-R-17- X-9,10-seco-A-gonatetraene 9 one (VIII), which is subjected to the action of anacidic cyclization agent, and the desired 3 methoxy-l3fl-R-Agonapentaene-17-one (IX) is isolated.

As it has been stated above, a considerable advantage of the presentprocess lies in the fact that it allows the recovery of the undesiredisomer obtained at the time of the resolution. For this purpose, thisisomer is subjected to the action of an aqueous acid, which induces thecleavage of the ketal function and isomerization to give 3-(l-R-2',5'-dioxo-cyclopentyl)-propionic acid (Vc), inactive by nature.This compound (Vc) is then converted into dl-3(1'-R-2'-X'-5-oxo-cyclopentyl)-propionic acid (V) by the action of aketalization agent, followed by an aqueous alkaline treatment, thepurpose of which is to saponify the ester of the carboxyl function whichis intermediately formed. This results in the cyclic utilization of theundesired isomer in the overall synthesis.

Of the various modes of execution, the present process can becharacterized particularly by the following points:

(1) The alkalinity of the condensation medium of the condensing of2-R-cyclopentane-1,3-dione with an alkyl acrylate is assured by thepresence of a tertiary amine, such as triethylamine. The reaction ispreferably conducted in an anhydrous organic solvent such as ethylacetate.

(2) The ketalization agent, which is reacted with the alkyl3-(l-R-2',5-dioxo-cyclopentyl)-propionate (III) is an alkylene glycolhaving 2 to 4 carbon atoms or a dioxolane, such as methylethyldioxolanein the presence of ethylene glycol. The work is conducted in thepresence of an acid catalyst, such as p-toluene sulfonic acid ormethylsulfonic acid.

(3) The saponification of the alkyl dl-3-(1-R-2'-X-5'-oxo-cyclopentyl)-propionate (III) is effected with the aid of an aqueousalkaline base, for example an aqueous alkali metal hydroxide such assodium hydroxide or potassium hydroxide.

(4) The resolution of the dl-3-(1'-R-2-X-5'-oxocyclopentyl)-propionicacid (V) is realized with the aid of an optically active base, such ascinchonine, D()-threo-(1- p-nitrophenyl)-2-N,N-dimethylamino-propane1,3-diol or l-nor adrenaline. The salt of the acid of the natural configuration with the optically active base is separated and alkalinizedto release the desired acid. The optically active base is recovered byconventional methods.

(5) The lactonization agent employed to lactonize compound 5A is theanhydride of a lower alkanoic acid, such as acetic acid anhydride, inthe presence of an lk li 8 metal salt of a lower alkanoic acid, such assodium acetate.

(6) The condensation of the optically active lactone of 3(1-R-2-X-5'-hydroxy-4'-cyclopentenyl)-propionic acid (VI) with a3-m-methoxy-phenyl-propyl magnesium halide, such as the bromide, isconducted in an ether, such as tetrahydrofuran under customary Grignardcondensation methods, and the subsequent alkaline treatment is realizedwith the aid of a strong alkaline base, for example an alkali metalhydroxide in a lower alkanol such as methanolic potassium hydroxide. Asmall amount of water is preferable in the reaction mixture.

(7) The cyclization agent employed to cyclize compound VIII is a strongdehydrating acid, such as a mineral acid, for example sulfuric acid,hydrochloric acid and phosphoric acid, or an organic acid, for example asulfonic acid.

(8) The cyclization agent is preferably a mixture of phosphoric acid andphosphoric acid anhydride. The work is carried out at a temperature ofabout 70 C.

The invention also includes a variant of the process, described in thepreceding, wherein the alkyl acrylate (II) is replaced by acrylonitrile.The condensation of acrylonitrile with 2 R-cyclopentane-1,3-dione (I) inalkaline medium is conducted in the same manner and gives 3-(1- R 2',5dioxo-cyclopentyl)-propionitrile, which is subjected to the action of aketalization agent in the same manner as described above. Thethus-formed dl-3-(1-R- 2-X'-5'-oxo-cyclopentyl)-propionitrile issaponified with a strong alkaline agent in the same manner as describedabove, thus obtaining dl 3 (1-R-2'-X'-5-oxo-cyclopentyl)-propionic acid(V), and the synthesis is pursued as previously described.

Moreover, in a general manner, the present invention also relates, as avariant of the process, to the utilization of a compound as startingmaterial, which was obtained as an intermediate product in any stage ofthe process, and to the realization of the remaining stages of theprocess.

The gonapentaenes, obtained according to the process of the inventioncan be easily converted into other steroid derivatives, endowed withinteresting pharmacological properties, such as 19-n0r-testosterone orl3}8-ethyl-l8,l9- dinor-testosterone as described in the examples.

Besides when R is CH R R R R are hydrogen and R is methyl, the finalcompound can be converted into 7-methyl-estrone which is the startingmaterial for the synthesis of a number of l9-nor 7-methyl-steroids asindicated by G. Anner (Chemia 20, 1966, pp. 434-435). When R is methyl,R is methyl or ethyl, R R R R are hydrogen and R is methyl, the finalcompound can be converted into 6-methyl, 13-methyl or ethyl estradiolderivatives from which 6-methyl physiologically active compounds can beobtained (B.F. 1,465,484 and Douglas Tetrahedron 1966, p. 1,019).

When R is methyl, R is hydrogen, R and R are methoxy, R is methyl, R andR are both hydrogen, the resulting estra-pentaene is a starting materialfor producing 2,3,4-trimethoxy-A -estratriene-l7fl-ol which is a potentanalgesic.

For anyone skilled in the art, it is obvious that, according to theoptically active base selected for the resolution of the racemic acid ofthe Formula V, either one or the other of the two epimers possible ispreferentially isolated. This allows the obtention, if so desired, notonly of the steroids of the natural series, but also in their antipodes.It is also obvious to those skilled in the art that the resolution stepcan be omitted and the racemic mixture of the final steroids can beobtained.

In addition, as a variant of the process of the invention, it should benoted that, at the time of the execution of this process, the reactionproduct, formed by condensation of the optically active lactone of3-(l-R-2'-X'-5- hydr0xy-4-cyclopentenyl)-propionic acid with a halide of3-m-methoxy phenyl-propyl magnesium, can be converted in one single stepinto 3-methoxy-13-R-A gonapentaene-17-one by the action of a cyclizationagent.

The following examples will serve for better comprehension of theinvention. However, it is to be understood that they do not limit thescope of the invention in any manner.

EXAMPLE l.--PREPARAT:ION OF LEVOROTA- TORY 3 METHOXY A ESTRAPEN-TAENE-l7-ONE Step A.Preparation of ethyl3-(1-methyl-2,5-dioxocyclopentyl)-propionate Under an atmosphere ofnitrogen, 50 gm. of 2-methylcyclopentane-l,3-dione, 125 cc. of ethylacetate, 240 cc. of ethyl acrylate and 118 cc. of a 20% solution oftriethylamine in ethyl acetate were introduced into 125 cc. of anhydrousethyl acetate. The mixture was brought to reflux, which was maintainedfor 19 hours. Thereafter, the mixture was concentrated to dryness underreduced pressure, the residue was rectified, and 86.54 gm. of ethyl3-(1'- methyl-2',5-dioxo-cyclopentyl)-propionate were obtained. Thecompound had a boiling point of 117 1 19 C. under a pressure of 0.55 mm.of mercury.

The product obtained was a liquid having an index of refraction, n=1.4685.

Analysis. Calculated for C H molecular weight=212.24 (percent): C,62.24; H, 7.6. Found (percent): C, 62.2; H, 7.7.

Step B.-.Preparation of ethyl dl-3-(1-methyl-2',2'-

ethylenedioxy- -oxo-cyclopentyl) -propionate Under an atmosphere ofnitrogen, first 0.750 gm. of monohydrated paratoluene sulfonic acid,then 21.2 gm. of ethyl 3-(1'-methyl-2,5-dioxo-cyclopentyl)-propionatewere introduced into a mixture consisting of 200 cc. of benzene, 200 cc.of methylethyldioxolane and 3 cc. of ethyleneglycol. The mixture wasagitated over a period of seven days at room temperature. Thereafter,1.2 cc. of triethylamine were added to the reaction mixture. Benzene waseliminated by distillation, then ethyl acetate was added. The organicsolution obtained was washed first with a saturated aqueous solution ofsodium bicarbonate, then with a saturated aqueous solution of sodiumchloride, and finally with water. Next, the solution was dried andconcentrated to dryness.

The residue was rectified under reduced pressure, obtaining thus 16.78gm. of ethyl dl-3-(l'-methyl-2,2'-ethylenedioxy-5'-oxo-cyclopentyl)-propionate. The prodnot had a boilingpoint of 130-l32 C. under a pressure of 0.15 mm. of mercury.

This product was a liquid with a refraction index, n =1.473.

Analysis. Calculated for C H O molecular weight-1256.29 (percent): C,60.91; H, 7.86. Found (percent): C, 61.0; H, 7.6.

This product is not described in the literature.

Step C.Preparation ofdl-3-(1'-methyl-2',2'-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acidUnder an atmosphere of nitrogen, 12 gm. of ethyl d13-(1'-methyl-2',2'-ethylenedioxy-5-oxo-cyclopentyl)- propionate wereintroduced into a mixture of 48.5 cc. of water and 30 cc. of a 2 Naqueous solution of sodium hydroxide. The mixture was agitated for 1hour and 45 minutes at room temperature, then cooled to 0 C., and the pHof the reaction medium was adjusted to about .8 by an addition of aaqueous solution of potassium acid sulfate. The aqueous phase wasextracted with ethyl ether and these extracts were eliminated. Next, thepH of the aqueous solution was adjusted to 4.0 by an addition ofpotassium acid sulfate. The reaction medium was saturated with sodiumchloride, extracted with ethyl ether and the ether extracts werecombined. The solution obtained was washed with a saturated aqueoussolution of sodium chloride, dried and concentrated to dryness.

The resultant residue was crystallized from a mixture of isopropyl etherand petroleum ether, thus obtaining 8.85 gm. ofdl-3-(1'-methyl-2,2-ethylenedioxy-5'-oxocyclopentyl)-propionic acid. Theproduct had a melting point of 66 C.

A sample of this product was purified by a new crystallization from amixture of isopropyl ether and petroleum ether. The crystallized samplehad a melting point of 66 C.

Analysz'.!.-Calculated for C H O molecular weight =228.24 (percent): C,57.88; H, 7.06. Found (percent): C, 57.7; H, 6.9.

This product is not described in the literature.

Step D.Resolution (1) by cinchonine (9.) Formation of the cinchoninesalt of the dextrorotatory 3-1'-methyl-2,2-ethylenedioxy-5'-oxo-cyclopentyl)- propionic acid.-11.6gm. of a cinchonine base were introduced into 180 cc. of ethanol. Themixture was agitated for 15 minutes at room temperature then brought toreflux under agitation, and 10 gm. of dl-3-(1'-methyl-2',2'-ethylenedioxy-5' oxo cyclopentyl) propionic acid were introducedinto the reaction mixture, which was then agitated for 10 minutesfurther while being maintained at reflux. Thereafter, cc. of the ethanolwere eliminated by distillation. Next, the reaction mixture was broughtto a temperature of 20 C. and agitated at this temperature for 1 hour.Then the temperature of the reaction mixture was reduced to atemperature ranging between 0 and +5 C., and the reaction mixture wasagitated at this temperature for 2 hours. Thereafter it was allowed tostand for 15 hours while this temperature was maintained. Theprecipitate formed was separated by filtration and washed with coldethanol. In this manner, 15.4 gm. of raw d-cinchonine salt wereobtained, having a specific rotation of [a] =+1l9 (c.=1% in ethanol).This product was purified by recrystallization from ethanol, thusobtaining the dextrorotatory cinchonine salt of 3-(1'-methyl2,2'-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acid. The product had amelting point of 186 with a specific rotation of [a] =+1Z7.5 (c.=1% inmethanol).

Circular dichroism: (ethanol) at 295 Ill 1., Ae=+l.25

This product is not described in the literature.

(b) Isolation of the dextrorotatory d-3-(1'-methyl-2',2'-ethylenedioxy-5-oxo-cyclopentyl)-propionic acid.5 gm. of thedextrorotatory cinchonine salt of 3-(1-methyl-2',2'-ethylenedioxy-5'-oxo-cyclopentyl) propionic acid were placed insuspension in 25 cc. of water. Then under agitation, 1.13 gm. of a 10.7N aqueous ammonium hydroxide solution were added, dropwise, and thesolution was agitated for 30 minutes at room temperature. The insolublematter was eliminated by filtration. The filtrate obtained was saturatedwith sodium chloride and acidified to a pH of 4.0 with an aqueoussolution of potassium acid sulfate. The aqueous phase was extracted withether. The ethereal solutions were combined and the organic solutionobtained was washed with a saturated aqueous solution of sodiumchloride, then dried and concentrated to dryness. The resultant residuewas purified by crystallization from a mixture of isopropyl ether andhexane, thus obtaining d 3 (1 methyl 2,2' ethylenedioxy 5oxo-cyclopentyl)-propionic acid. The product had a melting point of70-71 C. and a specific rotation [a] =+9.3 (c.= 1.1% in dioxane).

Circular dichroism: (ethanol) at 302 m Ae=+0'.58

This product is not described in the literature.

(c) Isolation and recovery of the undesired isomer. The residualcinchonine salts, resulting from the resolution and obtained bydistillation to dryness of the liquors of crystallization of thediastereoisomer corresponding to the dextrorotatory acid, weredecomposed, and the raw free acid was separated as indicated in thepreceding paragraph (b).

In this manner, 16 gm. of cinchonine salts produced 7.5 gm. of raw acid,which was treated under agitation for 15 minutes at 95 to 100 C. with 75cc. of water and 19 cc. of N sulfuric acid, then cooled, vacuum filteredand washed. Thus, the 3-(1'-methyl-2,5'-dioxo-cyclopentyl)- propionicacid (inactive by nature) was obtained, having a melting point of 126 C.

9.2 gm. of the acid, previously obtained and having a melting point of126 C., were treated over a period of 135 hours under agitation and at atemperature of 20 C. with 100 cc. of methylethyldioxolane, 100 cc. ofanhydrous benzene, 1.5 cc. of ethyleneglycol and 0.375 gm. ofp-toluenesulfonic acid.

Thereafter, 0.62 cc. of triethylamine were added to the reactionsolution, which was then Washed with water and distilled to dryness. Theresidue obtained was treated under vigorous agitation for hours at 25 C.with 48 cc. of water and 35 cc. of 2 N sodium hydroxide. The pH wasadjusted to 8 by an addition of aqueous KHSO (about 26 cc.), and thereaction solution was extracted with methylene chloride.

The separated aqueous solution was admixed with gm. of NaCl, cooled to+5 C. and adjusted to a pH of 3.5 to 4 by an addition of 10% aqueousKHSO, (about 38 cc.). The mixture was extracted with ether and theextract was distilled to dryness. The residue, crystallized fromisopropyl ether and petroleum ether, supplied dl-(1'-methyl-2',2'-ethylenedioxy-5-oxo-cyclopentyl) propionic acid. Theproduct obtained had a melting point of 66 C., identical to the productpreviously obtained.

Resolution (2) by D -threol-p-nitrophenyl) -2-N,N-dimethylamino-propane-1,3-diol (a) Preparation of theD(-)-threo-(1-p#nitrophenyl)-2- N,N-dimethylamino-propane-1,3-diol saltof the dextrorotatory 3(1'-methyl-2',2-ethylene-dioxy-5'-oxo-cyclopentyl)-propionic acid.5 gm.of dl-3-(l'-methyl-2,2'- ethylenedioxy-S-oXo-cyclopentyl)-propionic acidwere introduced into cc. of methanol, then 5.35 gm. of D()-threol-p-nitrophenyl)-2-N,N-dimethylamino-propane-1, 3-diol (describedin copending, commonly-assigned US. patent application Ser. No. 610,219,filed Jan. 19, 1967 and French Pat. No. 1,481,978) were added, and themixture was agitated for 1 hour and 45 minutes at room temperature. Itwas then allowed to stand for 15 hours at +5 C. The precipitate formedwas vacuum filtered, washed with methanol and dried. The raw productthus obtained was purified by crystallization from methanol and 3.6 gm.of the D()-threo-(l-p-nitrophenyl)-2-N,N-dimethylamino-propane-1,3-diolsalt of the dextrorotatory 3-(1-methyl-2',2-ethylenedioxy 5'-oxocyclopentyl)- propionic acid were obtained. The product had a meltingpoint of 145 C. and a specific rotation of [a] =l9.7 (c.=0.9% inmethanol).

Circular dichroism (in ethanol) Ae=+0.47 at 297 m This product is notdescribed in the literature.

(b) Decomposition of the salt and obtention of the dextrorotatory3-(1-methyl-2',2-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acid.2 gm.of the D(-)-threol-p-nitrophenyl)-2-N,N-dimethylamino-propane-1,3-diolsalt of the dextrorotatory 3-(1'-methyl-2',2-ethylenedioxy-5-oxo-cyclopentyl)-propionic acid, as previously prepared, wereintroduced into a mixture of 10 cc. of water and 0.4 cc. of 10.7 Naqueous ammonium hydroxide solution. Next, the mixture was agitated for1 hour at room temperature, the insoluble, which is constituted by D()threo (l-p-nitrophenyl) 2 N,N-dimethylamino-pro pane-1,3-diol, wasvacuum filtered, then washed first with water, then with normal sodiumhydroxide and again with water. These wash liquors were combined withthe filtrate obtained. This filtrate was then extracted with ethylacetate to completely eliminate any base still present. The aqueousfiltrate was saturated with sodium chloride and acidified, to obtain apH of 3.5 to 4.0, with an aqueous solution of 12 potassium acid sulfate.The aqueous solution with a pH of 3.5 to 4.0 was extracted with ethylacetate. The extracts were combined, washed with water saturated withsodium chloride, dried and finally concentrated to dryness under reducedpressure.

The residue was crystallized from isopropyl ether, thus obtaining 0.725gm. of dextrorotatory 3-(1'-methyl-2,2- ethylenedioxy-5-oxo-cyclopenty1)propionic acid. The product had a melting point of 70 -71 C. and aspecific rotation [a] =+9.3 (c.=1.1% in dioxane),

Circular dichroism (in dioxane) As at 302 rn,u=+0.58

This product is identical to the dextrorotatory 3-(1'- methyl2',2'-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acid, described in thepreceding.

After the methanolic mother liquors of formation and crystallization ofthe salt obtained in (a) had been concentrated to dryness, the rawD()-threo-(1-p-nitrophenyl)-2-N,N-dimethylamino-propane-1,3-diol salt ofthe levorotatory 3-1'-methyl-2,2'-ethylenedioxy-5-oxo-cyclopentyl)-propionic acid wasobtained. Starting with this product, the levorotatory acid wasprepared, employing a technique analogous to that previously employedfor the obtention of the dextrorotatory acid.

The levorotatory acid had a melting point of 70 to 71 C. and a rotatorypower of 9.3 (c.=1.1% in dioxane). It could be racemized in a manneranalogous to that previously described.

Step E.Preparation of the levorotatory lactone of 3-(1'-methyl-2,2'-ethylenedioxy 5' hydroxy 4' cyclopentenyD-propionic acidUnder an atmosphere of nitrogen, first 0.078 gm. of anhydrous sodiumacetate, then 6.5 gm. of dextrorotatory 3(1'-rnethy1-2',2-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acid wereintroduced into 97 cc. of acetic acid anhydride. The mixture Was broughtto reflux and maintained at reflux for 20 hours. Thereafter, 20 cc. ofacetic acid anhydride were added, then the reaction mixture was slowlydistilled under normal pressure, until cc. of distillate had beenrecovered. Next, the reaction mixture was concentrated to dryness underreduced pressure. The residue was dissolved in ethyl ether, the etherealsolution was washed first with an aqueous solution of sodiumbicarbonate, then with water, dried and concentrated to dryness.

The residue was subjected to chromatography through silica gel, thusobtaining 1.31 gm. of the levorotatory lactone of3-(1'-methyl-2',2'-ethylenedioxy-5-hydroxy-4'-cyclopentenyl)-propionicacid. The product had a melting point of 56 C., and a specific rotation[a] =134.5 (c.=1.02% in dioxane).

Circular dichroism (in ethanol) at 229 mu, Ae=10.99

This product is not described in the literature.

Step F.Preparation of 3methoxy-17,17-ethylenedioxy- 9,10-seco-A-estratetraene-9-one (a) Preparation of 3-(m-methoxyphenyl)-propylmagnesium bromide.In an inert atmosphere, 1.06 gm. of magnesium shavingsand a small crystal of iodine were introduced into a dry container. Themixture was heated over a flame until the iodine Was sublimated, thenthe mixture was allowed to cool. Within the space of about 30 minutes atto C., a solution of 10 gm. of 1- brorno-3-(tn-methoxyphenyl)-propanedissolved in 40 cc. of tetrahydrofuran was introduced, after havingfirst started the reaction by the rapid introduction of a small amountof the solution of the brominated derivative. The reaction mixture wasagitated over a period of 2 hours, obtaining a solution of3-(m-methoxyphenyl)-propyl magnesium bromide which had a titer of 0.42moi/liter.

(b) Condensation of 3 (m methoxyphenyl) propyl magnesium bromide withthe levorotatory lactone of 3- (l-methyl-2',2-ethylenedioxy 5'hydroxy-4-cyclopentenyl)-propionic acid.In an inert atmosphere, 0.87 gm.of the levorotatory lactone of 3-(l-methyl-2,2-ethylenedioxy-5'-hydroxy4' cyclopentenyl)-propionic acid were introduced into 20 cc. oftetrahydrofuran. The temperature of the reaction mixture was brought to55 C., then, dropwise, 14.8 cc. of a 0.42 M solution of3-(mmethoxyphenyl)-propyl magnesium bromide in tetrahydrofuran wereadded. The mixture was agitated for 30 minutes at 55 C., then thetemperature was allowed to raise to 20 C. within 25 minutes. Thistemperature was maintained for 15 minutes. Thereafter, the reactionmixture was cooled to -55 C., and 10 cc. of a saturated aqueous solutionof ammonium sulfate and 50 cc. of ethyl ether were added thereto. Theethereal phase was decanted and washed with water. The aqueous phaseswere extracted with benzene and the organic phases were combined, washedwith a saturated aqueous solution of sodium chloride, dried andconcentrated to dryness. In this manner, 2.17 gm. of product wereobtained.

(c) Alkaline treatment-2.17 gm. of the product obtained in (b) wereintroduced into a mixture of 22 cc. of 1.36 N potassium hydroxide inmethanol and 1.5 cc. of water. The mixture was brought to reflux andmaintained at reflux for /2 hour. Then the mixture was cooled, ice wasadded thereto and the pH was adjusted to 8 by an addition of aceticacid. Next, the reaction mixture was extracted with ethyl acetate. Theextracts were washed with a saturated aqueous solution of sodiumchloride, dried and evaporated to dryness. The resultant residue waspurified by chromatography through silica gel, thus obtaining 0.56 gm.of 3-methoxy-17,17-ethylenedioxy-9,l-sec-A -estratetraene-9-one.

Ultra-violet spectra (in ethanol) max.: 252 mu, e=7,940

This product is not described in the literature.

Step G.Preparation of methyl ether of 8,9-14,1S-bis-dehydro-estrone Atroom temperature and in an inert atmosphere, 0.520 gm. of3-methoxy-17,17-ethylenedioxy-9,10-seco- A -estratetraene-9-one(optically active) were introduced into 6 gm. of a mixture of gm. ofphosphoric acid anhydride and 8 cc. of an 85% phosphoric acid solution.This mixture was agitated for 30 minutes at 75 C. Next, the reactionmixture was cooled and ice was added thereto. The mixture was againagitated for 10 minutes and then extracted with ethyl acetate. Theorganic solutions of the extraction were combined. The organic solutionobtained was washed first with an aqueous solution of sodiumbicarbonate, then with water, dried and concentrated to dryness.

The residue was subjected to chromatography through a 'bed of silica,thus obtaining levorotatory 3-methoxy- A -estrapentaene-l7-one for themethyl ether of 8,9-14,l5-bis-dehydro-estrone). The product had amelting point of 142 C. and a specific rotation of [a] =100 (c.=0.5% inchloroform).

The levorotatory 3 methoxy-A -estrapentaene-17-one could be convertedinto 19-nor-testosterone in the following manner:

Step A.-Methyl ether of 8,9-dehydro-estrone 150 cc. of acetonecontaining 2% of pyridine and 1.2 gm. of alumina containing 5% ofpalladium were introduced into a hydrogenation apparatus. The apparatuswas then purged. The mixture was agitated for 2 hours and 30 minutesunder an atmosphere of hydrogen. Thereafter while avoiding any contactwith atmospheric air, a deoxygenated solution of 6 gm. of levorotatory3-methoxy- A -estrapentaene-17-one (or the methyl ether of8,9-14,1S-bis-dehydro-estrone) in 450 cc. of acetone containing 2% ofpyridine was introduced into the apparatus. The mixture was agitatedunder an atmosphere of hydrogen, and within the space of 2 hours about525 cc. of hydrogen were absorbed. Next, the apparatus was purged withnitrogen and the catalyst was removed by filtration. The acetonicsolution was concentrated to dry- 14 ness, and 6 gm. of raw product wereobtained, having a melting point of 120 C.

This raw product was purified by crystallization from ethanol, thusobtaining the dextrorotatory 3-methoxy- 41 -estratetraene-17-one, (orthe methyl ether of 8,9-dehydro-estrone). This product had a meltingpoint of 128 C. and a specific rotation of [a] :+29 (c.: 1% inchloroform).

Ultra-violet spectra (in ethanol) A at 211 mu $18,050 r at 279 mu516,350

Step B.19-nor testosterone At a temperature of 70 C., a solution of 0.15gm. of the methyl ether of 8,9-dehydro estrone in 11 cc. oftetrahydrofuran and 0.1 cc. of ethanol were added to 30 cc. of liquidammonia. Within the space of 3 hours and 30 minutes, 0.12 gm. of lithiumin small pieces and 1 cc. of ethanol in fractions of 0.1 cc. were added.This addition was followed by an addition of 2 cc. of ethanol, then 10cc. of water. The ammonia was then removed. The reaction mixture wastaken up in methylene chloride, washed with water and distilled undervacuum. The residue was then taken up in 10 cc. of methanol and 2 cc. ofconcentrated hydrochloric acid. The mixture was heated at reflux for 25minutes, diluted with water and extracted with methylene chloride. Theextracts were washed and distilled to dryness. In this manner, 0.148 gm.of product was obtained, which, purified by chromatography, supplied19-nor-testosterone with a yield of about 50%. The product was identicalto a sample prepared by a dijferent method.

EXAMPLE 2.PREPARATION OF DL-3-(l'-METH- YL 2.,2 ETHYLENEDIOXY 5OXOCYCLO- PENTYL) 'PROPIONIC ACID BY CONDENSA- TION OF2-METHYICYCLOPENTANE 1,3 DI- ONE WITH AC-RYLONITRILE StepA.--Preparation of 3-(l'-methyl-2,5'-di0xo-cyclopentyl -propionitrileOver a period of '64 hours, 20 gm. of Z-methylcyclopentane-1,3-dione incc. of ethyl acetate containing 1 0% of triethylamine and 58.5 cc. ofacrylonitrile were heated at reflux. Thereafter, the solvents and theexcess of the reactant were evaporated under vacuum. The residual oilwas distilled under a pressure of 0.2 to 0.3 mm. of mercury. 22 gm. of3-(1'-methyl-2,5'-dioxo-cyclopentyl)-propionitrile were recoveredpassing over at 136 to 140 C.

Analysis.Calculated for C H O N; molecular weight ='1-65.19 (percent):C, 65.43; H, 6.71; N, 8.48. Found (percent): C, 65.2; H, 6.7; N, 8.4.

Step B.Preparation ofdl-3-(1'-methyl-2',2-ethylenedioxy-5'-oxo-cyclopentyl)-propionitrileOver a period of 9 hours, 5 gm. of 3-(1'-methyl-2,5'-dioxo-cyclopentyl)-propionitrile in 50 cc. of methylethyldioxolanecontaining 2% of ethyleneglycol and 1 gm. of p-toluenesulfonic acid wereagitated at a temperature of 20 C. Then, 2 cc. of triethylamine wereadded and the mixture was diluted with water. The reaction mixture wasthen extracted with methylene chloride, the extracts were Washed withwater and distilled to dryness. In this manner, 6.5 gm. ofdl-3-(1'-methyl-2',2'-ethylenedioxy-5-oxocyclopentyl)-propionitrile wererecovered.

This product is not described in the literature.

Step C.-Preparation of dl-3-(1'-methyl-2,2-ethylenedioxy-5'-oxo-cyclopentyl) -propionic acid Under agitation, 1 cc. ofethyleneglycol, 2 cc. of water and 0.5 cc. of a potassium hydroxidesolution (containing 700 gm./liter) were heated for 15 minutes at 100 toC. with 0.3 gm. ofdl-3-(1'-methyl-2',2-ethylenedioxy-5-oxo-cyclopentyl)-propionitrile. Themixture was cooled and extracted with methylene chloride. The sepa- 15rated aqueous solution was acidfied to a pH of 3.5 to 4 by an additionof KHSO and then extracted with ethyl acetate. The organic extract,brought to dryness, supplied dl-3-(1-methyl-2',2-ethylenedioxy-5-oxocyclopenty'l)- propionic acid, identical to the product obtainedaccording to Example 1, Step C.

EXAMPLE 3.PREPARATION OF 3 METHOXY- 13 3-ETHYL A GONAPENTAENE-17- ONEStep A.Preparation of ethyl 3-( 1-ethyl-2,5-dioxocyclopentyl) propionate200 gm. of 2-ethyl-cyclopentane 1,3-dione were introduced into a mixtureof 1000 cc. of ethyl acrylate and 1000 cc. of ethyl acetate containingof triethylamine. Under an atmosphere of nitrogen, the reaction mixturewas brought to reflux, and maintained at reflux for 21 hours.Thereafter, the solution obtained was concentrated to dryness underreduced pressure. The resultant residue was rectified under vacuum.

321 gm. of ethyl 3-(1-ethyl-2,5'-dioxo-cyclopentyl)- propionate wereobtained, having a boiling point of 126 C. under a pressure of 0.5 mm.of mercury n =1.470O.

This compound is not described in the literature.

Step. B.Preparation of ethyldl-3-(l-ethyl-2,2'-ethylenedioxy-5'-oxo-cyclopentyl) propionate 6 gm. ofparatoluene sulfonic acid and 200 gm. of ethyl 3-(l-ethyl-2',5'dioxo-cyclopentyl)propionate were introduced into a mixture of 2000 cc.of methylene chloride, 2000 cc. of methylethyldioxolane and 50 cc. ofethyleneglycol. Under an atmosphere of nitrogen, the reaction mixturewas brought to reflux while recycling the condensate through a column ofdehydrating material, such as alkaline alumino silicate. The reactionmixture was maintained at reflux over a period of 12 days whilereplenishing the dehydrating agent and introducing three times into thereaction mixture, 1.5 gm. of paratoluene sulfonic acid and 10 gm. ofethyleneglycol. Thereafter, the reaction mixture was cooled and renderedalkaline with triethylamine. The organic solution was washed first witha saturated aqueous solution of sodium bicarbonate, then with water. Theaqueous extracts were combined and extracted with methylene chloride.This chloromethylenic extract was added to the principal organicsolution. The organic solution obtained was dried and concentrated todryness under reduced pressure. Thus, 248.4 gm. of raw ethyl3-(1'-ethyl-2,2-ethylenedioxy-S-oxocyclopentyl)-propionate (product A)were obtained. This product was utilized as such for the obtention ofthe free acid.

A sample of this product was rectified under reduced pressure. Itsboiling point was 160 C. under a pressure of 2.5 mm. of mercury, n:1.479O.

This compound is not described in the literature.

Step. C.Preparation ofdl-3-(1'-ethyl-22'-ethylenedioxy-5'-oxo-cyclopentyl)propionic acid 248.4gm. of the product A, obtained in the preceding step, were introducedinto 1430 cc. of a 2 N aqueous solution of sodium hydroxide. Then thereaction mixture was agitated for 3 hours at room temperature.Thereafter, the reaction mixture was cooled to +5 C. and brought to a pHof 9.0 by an addition of an aqueous solution of potassium acid sulfate.Next, the alkaline aqueous solution was extracted with ether and thensaturated with sodium chloride. The temperature of the aqueous solutionwas maintained at +5 C. and the pH was adjusted to 4.0 by an addition ofan aqueous solution of potassium acid sulfate. The aqueous acidicsolution was extracted with ether while re-adjusting the pH to 4.0 aftereach extraction. The ethereal extracts were washed with a saturatedaqueous solution of sodium chloride, then dried, decolorized with animalcarbon black and concentrated to dryness under reduced pressure. Next,the residue was crystallized from isopropyl ether, thus obtaining in twoyields, 148.6 gm. of 3-(1- ethyl-2',2-ethylenedioxy-5'-oxo-cyclopentyl)propionic acid. The product had a melting point of 76 C. to 77 C.

A sample of this product was recrystallized from isopropyl ether to givea melting point of 77 C.

By dissolution in ethyl acetate and an addition of 2,5-diphenyl-piperazine, the 2,5-diphenyl-piperazine salt of3-(1-ethyl-22'-ethylenedioxy-5-oxo-cyclopentyl) propionic acid wasobtained. The melting point of this product was 142 C. and the nitrogentiter of the product was 3.8 gm./ gm. (theoretical 3.82).

This compound is not described in the literature.

Step D.Resolution (a) Formation and isolation of the salt of thelevorotatory nor-adrenaline and of the dextrorotatory 3-(lethyl 22'ethylenedioxy-S-oxo-cyclopentylpropionic acid.30 cc. of hot water werepoured over a mixture of 20 gm. ofdl-3-(1-ethyl-2,2'-ethylenedioxy-5'-oxo-cyclopentyl)-propionic acid andof 14 gm. of levorotatory 2- amino-1-(3,4-dihydroxyphenyl)-ethanol.Under agitation, the reaction mixture was heated in a water bath. Thesmall amount of insoluble residual matter was eliminated by filtration.Crystallization was initiated by scraping and maintaining the solutionat 0 C. over a period of 48 hours, in the total absence of light. Theprecipitate formed was isolated by vacuum filtering, triturated in anaqueous solution of sodium chloride and dried under reduced pressure.This raw product was purified by three successive recrystallizationsfrom an aqueous solution of sodium chloride, thus obtaining 9.4 gm. ofthe levorotatory nor-adrenaline base salt of the dextrorotatory3-(1'-ethyl 2,2' ethylenedioxy-S-oxo-cyclopentyl)-propionic acid. Thecompound had a melting point of 184 C. and a specific rotation [a] 26(c.=1% in water).

A sample of this product was crystallized from water and had a meltingpoint of C.

Circular dichroism (in ethanol) As at 288-290 I11/L:+0.34

This compound is not described in the literature.

By saturation of the mother liquors resulting from the crystallizationof the raw product in sodium chloride, by alkalization with ammoniumhydroxide, by vacuum filtration followed by washing the precipitateformed, the levorotatory nor-adrenaline base was recovercd. The producthad a melting point of 242 C., determined on the Kofler block.

(b) Isolation of the dextrorotatory 3-(l-ethyl-2,2'-ethylenedioxy-S'-oxo-cyclopentyl) propionic acid-4.68 gm. of thelevorotatory nor-adrenaline base salt of dextrorotatory 3(1'-ethyl-2,2-ethylenedioxy-5-oxo-cyclopentyl)-propionic acid with amelting point of 184 C., obtained in the preceding, were introduced into14.1 cc. of water. The mixture was agitated for 30 minutes at roomtemperature in the total absence of light. Next, the reaction mixturewas cooled to +5 C. under an atmosphere of nitrogen and the pH wasadjusted to 10.0 by an addition of an aqueous 22 B. ammonia solution.The reaction mixture was agitated, then kept at rest for 15 hours at 0C. The precipitate formed was isolated by vacuum filtration, washedfirst with a dilute aqueous ammonia solution, then with water andfinally dried. In this manner, 1.86 gm. of the levorotatorynor-adrenaline base were obtained.

The combined filtrate and wash waters were saturated with sodiumchloride under an atmosphere of nitrogen. The reaction medium was cooledto +5 C., the pH was adjusted to 3.5 by a progressive addition of anaqueous solution of sodium acid sulfate, whereby a precipitate appeared.The reaction mixture was extracted with ether. The combined otherextracts were washed with a saturated aqueous solution of sodiumchloride, dried and concentrated to dryness under an atmosphere ofnitro- 17 gen under reduced pressure. Thus, 2.62 gm. of dextrorotatory 3(1-ethyl-2',2-ethylenedioxy-5-oxo-cyclopentyl)-propionic acid wereobtained with a specific rotation [a] =-l-4.9 (c.=l% in dioxane).

Circular dichroism (in dioxane) As at 288-290 m =+0.11

This compound is not described in the literature.

(c) Isolation of the levorotatory3-(1-ethyl-2',2'-ethylenedioxy-S'-oxo-cyclopentyl)-propionic acid-By theaction of yohimbine on dl-3-(1'-ethyl-2,2'-ethylenedioxy-'-oxo-cyclopentyl) -propionic acid, the yohimbine salt of thelevorotatory 3 (1'-ethyl-2,2'-ethylenedioxy-5-oxocyclopentyl)-propionicacid was obtained, which was purified by crystallization from ethanol.The product had a melting point of 194 C.

Circular dichroism (in dioxane) Ae 285 ma -+1.4 A: 270 mp.=+1.7

This compound is not described in the literature.

The levorotatory acid was freed and purified by starting with theyohimbine salt in a fashion analogous to that utilized for the obtentionof the dextrorotatory acid by starting with the nor-adrenaline salt,thus obtaining levorotatory 3 (1' ethyl 2',2'ethylenedioxy-5-oxocyclopentyl)-propionic acid. The product had aspecific rotation [a] =5 (c.=1% in dioxane).

Circular dichroism (in dioxane) As at 296 m,u=0.10

This compound is not described in the literature.

Step E.Preparation of the levorotatory lactone of the dextrorotatory3-(1-ethyl 2,2 ethylene-dioxy-5- hydroxy-4-cyclopentenyl)-propionic acidIn an inert atmosphere, 20 mg. of sodium acetate and 1.53 gm. ofd-3-(1-ethyl 2',2 ethylenedioxy-5'-oxo cyclopentyl)-propionic acid,dextrorotatory, in dioxane, were introduced into 34 cc. of acetic acidanhydride. The reaction mixture was brought to reflux and then was veryslowly concentrated, in an inert atmosphere, in order to eliminatenearly half of the acetic acid anhydride within the space of abouthours. Thereafter, the reaction mixture was cooled, and benzene and 0.10cc. of pyridine were added thereto. The reaction medium was thenconcentrated to dryness, under reduced pressure and an inert atmosphere.The residue was admixed with methylcyclohexane and concentrated todryness under the same conditions as previously described. This processwas repeated several times in succession. The resultant residue wasdissolved in a mixture of benzene and ether. The organic solution waswashed first with an aqueous solution of sodium bicarbonate, then withwater, dried and concentrated to dryness. The resultant residue was thenpurified by chromatography through silica gel, thus obtaining 1.27 gm.of raw levorotatory lactone of the dex trorotatory d-3-(1' ethyl 2',2ethylenedioxy-5'-hydroxy 4' cyclopentenyl)-propionic acid, with aspecific rotation [u] =110.5 (c.=1% in dioxane).

Circular dichroism (in ethanol) Ae=-12.1 at 227 mp. Ae=+0.42 at 305 mpThis compound is not described in the literature.

Step F.-Preparation of 3-rnethoxy 13B ethyl-17,17- ethylenedioxy 9,10seco-A gonatetraene- 9-0ne (a) Preparation of 3 (m methoxyphenyl) propylmagnesium bromide.In an inert atmosphere, 1.06 gm. of magnesium shavingsand a small iodine crystal were introduced into a dry reaction vessel.The mixture was heated over a flame until the iodine was sublimated,then it was allowed to cool. At a temperature of 40 to 45 C. and withinabout 30 minutes, a solution of 10 gm. of 1 bromo 3 (m methoxyphenyl)propane dissolved in 40 cc. of tetrahydrofuran was introduced therein,after having previously initiated the reaction by the rapid introductionof a small quantity of the brominated derivative solution. The reactionmixture was agitated for 2 hours, thus obtaining a solution of 3-(m-methoxyphenyl)-propylmagnesium bromide, which titrated 0.42mol/liter.

(b) Condensation of 3 (m-methoxyphenyl)-propyl magnesium bromide withthe levorotatory lactone of 3- (1' ethyl 2',2' ethylenedioxy 5'hydroxy-4'-cyclopentenyl) propionic acid.In an inert atmosphere, 1.04gm. of levorotatory lactone of the dextrorotatory 3- (1' ethyl 2',2'ethylenedioxy 5' hydroxy 4' cyclopentenyl) propionic acid wereintroduced into 24 cc. of tetrahydrofuran. The temperature of thereaction mixture was adjusted to C. Then 17.8 cc. of a 0.42 M solutionof 3 (m methoxyphenyl) propyl magnesium bromide in tetrahydrofuran wereadded, dropwise. The reaction mixture was agitated for 30 minutes at 55C., then the temperature was allowed to rise to 20 C. within 25 minutesand this temperature was maintained for 15 minutes. The reaction mixturewas then cooled to 55 C., and 12 cc. of a saturated aqueous solution ofammonium sulfate and cc. of ethyl ether were added. The ethereal phasewas separated by decanting and washed with water. The aqueous phaseswere extracted with benzene. The organic phases were combined, washedwith a saturated aqueous solution of sodium chloride, dried andconcentrated to dryness.

(c) Alkaline treatment The residue obtained in (b) was introduced into amixture of 26.4 cc. of 1.36 N methanolic potassium hydroxide and 1.8 cc.of water. The mixture was brought to reflux, which was maintained for /2hour. Then the mixture was cooled by adding ice, and the pH was adjustedto 8 by addition of acetic acid. The reaction mixture was extracted withethyl acetate. The extracts were washed with a saturated aqueoussolution of sodium chloride, dried and evaporated to dryness. Theresidue was purified by chromatography through silica gel, and theoptically active 3 methoxy 13 8 ethyl 17,17 ethylenedioxy 9,10- secoA1,3,5(1)'8(14) gonatetraene 9 one was obtained.

This product is not described in the literature.

Step G.Preparation of 3-methoxy-l3fi-ethyl- A -gonapent-aene-17-one Atroom temperature and in an inert atmosphere, 0.728 gm. of opticallyactive 3-methoxy-13,6-ethyl-17,17-ethylenedioxy-9,1O-seco-A-gonatetraene-9-one were introduced into 8.4 gm. of a mixture of 10 gm.of phosphoric acid anhydride and 8 cc. of phosphoric acid solution. Thismixture was agitated for 30 minutes at 75 C. Next, the reaction mixturewas cooled, ice was added, and the mixture was agitated for 10 minutesand then extracted with ethyl acetate. The organic solutions of theextraction were combined. The organic solution obtained was washed firstwith an aqueous solution of sodium bicarbonate, then with water, driedand concentrated to dryness.

The resultant residue was subjected to chromatography through a bed ofsilica, thus obtaining the optically active S-methoxy-l3/3-ethyl-A-gonapentaene-l7-one.

This optically active compound is not described in the literature.

The 3-methoxy-13/3-ethyl-A -gonapentaene-17- one could be converted into13B-ethyl-l8,19-din0r-testosterone in the following manner:

Step A.3-methoxy 13B-ethyl-A -gonatetraene- 17-one cc. of acetonecontaining 2% of pyridine and 0.84 gm. of alumina containing 5% ofpalladium were introduced into a hydrogenation apparatus. This apparatuswas purged, then, under an atmosphere of hydrogen, the mixture wasagitated for 2 hours and 30 minutes. Avoiding any contact with theatmospheric air, a deoxygenated solution of 4 gm. of optically active3-methoxy-13B-ethyl- A gonapentaene-17-one in 315 cc. of acetonecontaining 2% of pyridine was introduced into the apparatus. The mixturewas agitated in an atmosphere of hydrogen, and about 368 cc. of hydrogenwere absorbed within 2 hours. The apparatus was purged with nitrogen,the catalyst was removed by filtration, and the acetonic solution wasconcentrated to dryness.

This raw residue was purified by chromatography, thus obtaining theoptically active 3 methoxy 13B ethyl- A -gonatetraene-17-one.

This optically active compound is not described in the literature.

Step B.-13fi-ethyl-18,19-dinor-testosterone At a temperature of 70 C., asolution of 0.45 gm. of optically active 3-methoxy-13B-ethyl-A-gnatetraene-17-one in 33 cc. of tetrahydrofuran and 0.3 cc. of ethanolwere added to 90 cc. of liquid ammonia. In the space of 3 hours and 30minutes, 0.36 gm. of lithium in small pieces and 3 cc. of ethanol infractions of 0.3 cc. each were added, followed by the addition of 6 cc.of ethanol and 30 cc. of water. Next, the ammonia was removed. Thereaction mixture was taken up in methylenechloride, washed with waterand distilled under vacuum. The residue was taken up in 30 cc. ofmethanol and 6 cc. of concentrated hydrochloric acid and heated atreflux for 25 minutes. Thereafter the mixture was diluted with water andextracted with methylene chloride. The extracts were washed anddistilled to dryness. Thereafter, the residue was purified bychromatography, obtaining the dextrorotatory13j3-ethyl-18,19-dinor-testosterone.

This product was identical to a sample prepared according to a differentmethod.

EXAMPLE 4.--PREPARATION OF 3-METHOXY-7u- METHYL-A -ESTRAPENTAENE-l7-ONEStep A.Preparation of the magnesium reactant Under an atmosphere ofargon, and within the space of 30 minutes at a temperature of 25 C., asolution of 3 gm. of 1-bromo-2a-methyl-3(m-methoxyphenyD-propane, witha. specific rotation [a] =-35 (c.=1% in ethanol), in 14 cc. oftetrahydrofuran was added to 320 mg. of magnesium shavings. The mixturewas agitated for 2 hours, and a solution of2m-methy1-3-(m-methoxyphenyl)- propyl magnesium bromide was obtained,titrating 0.5 moi/liter.

Step B.Condensation of 2a-methyl-3-(m-methoxyphenyl)-propyl magnesiumbromide with the levorotatory lactone of3-(l'-methyl-2,2-ethylenedioxy-S'-hydroxy- 4-cyclopentenyl)propionicacid At a temperature of -70 C. and within the space of 30 minutes, 14cc. of the solution of the magnesium reactant, obtained in Step A, wereadded to 970 mg. of the levorotatory lactone of3-(1-methyl-2,2'-ethylenedioxy- -hydroxy-4'-cyclopentenyl)propionic acid(obtained in Step E in Example 1) in solution in 12 cc. oftetrahydrofuran and 3 cc. of toluene. The mixture was agitated for 3hours at 70 C. then the temperature was raised to 20 C. and the reactionmixture was maintained at this temperature for 1 hour and 30 minutes.Thereafter, the reaction mixture was cooled at 60" C. and the excess ofthe magnesium reactant was destroyed by an addition of ammonium sulfate.Next, the reaction mixture was extracted with ether and the oil obtainedwas purified by chromatography through silica gel. Thus, 200 mg. ofproduct were obtained.

Infra-red spectra: absorptions at 1,730 cm.- and 1,710

20 Ultra-violet spectra:

e=8,160 at 218 m, e=2,180 at 272273 mg 6=1,950 at 279-280 m StepC.Cyclization 0.5 cc. of concentrated sulfuric acid (66 B) was added tomg. of the product obtained in Step B. The mixture was agitated for 1hour and then was poured into a water-ice-sodium bicarbonate mixture.The reaction mixture was washed with water and evaporated to drynessunder vacuum. Thus, 34 mg. of 3-II1eth0XY-7ocmethyl-A-estrapentaene-17-or1e were obtained.

Ultra-violet spectra: absorption at 314 me where R is an alkyl having 1to 3 carbon atoms, R" is a lower alkylene having 2 to 4 carbon atoms, RR and R are substituents selected from the group consisting of hydrogen,lower alkyl and lower alkoxy, R is lower alkyl, R and R are substituentsselected from the group consisting of hydrogen, a-lower alkyl andfi-lower alkyl and the wavy line indicates either the a-configuration orthe ER-configuration.

2. A compound of claim 1 where R is CH R" is R R and R are hydrogen, Ris CH and R and R are hydrogen.

3. A compound of claim 1 where R is C H R is R R and R are hydrogen, Ris CH and R and R are hydrogen.

References Cited UNITED STATES PATENTS 3,027,409 3/1962 Hogg et al.260-3409 3,300,484 1/1967 Pappo 260-3409 OTHER REFERENCES Whitehurst eta1., Chemical Abstracts, vol. 67 (1967) Col. 91015f.

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner U.S.Cl. X.R.

